Chronic glucolipotoxic conditions in pancreatic islets impair insulin secretion due to dysregulated calcium dynamics, glucose responsiveness and mitochondrial activity

BMC Cell Biology

Madanahalli R Jagannath¹  Usha Narayanan¹  Korrapati Neelima¹  Rachapalli Smitha¹  Siddaraju Nethra¹  Puttrevana M Pallavi¹  Aggunda N Yateesh¹  Ashok Kumar Reddy¹  Pavagada C Shilpa¹  Sanghamitra Biswas¹  Anup Mammen-Oommen¹  Manoj Kumar Sadasivuni¹  Mahesh Kumar Verma¹  Baggavalli P Somesh¹ 

[1] Connexios Life Sciences Pvt Ltd.,, No. 49, First Main road, 3rd phase, JP Nagar, Bangalore 560 078, India

关键词: Insulin secretion;    Insulin content;    Glucose metabolism;    Glucolipotoxicity;    Rat islets;    Type 2 diabetes;   

Others  :  855211
DOI  :  10.1186/1471-2121-14-31

 received in 2012-10-17, accepted in 2013-06-24,  发布年份 2013

【 摘 要 】

Background

In the progression towards diabetes, glucolipotoxicity is one of the main causes of pancreatic beta cell pathology. The aim of this study was to examine the in vitro effects of chronic glucolipotoxic conditions on cellular responses in pancreatic islets, including glucose and fat metabolism, Calcium mobilization, insulin secretion and insulin content.

Results

Exposure of islets to chronic glucolipotoxic conditions decreased glucose stimulated insulin secretion in vitro. Reduced protein levels of Glut2/slc2a2, and decreased glucokinase and pyruvate carboxylase mRNA levels indicated a significant lowering in glucose sensing. Concomitantly, both fatty acid uptake and triglyceride accumulation increased significantly while fatty acid oxidation decreased. This general suppression in glucose metabolism correlated well with a decrease in mitochondrial number and activity, reduction in cellular ATP content and dampening of the TCA cycle. Further, we also observed a decrease in IP3 levels and lower Calcium mobilization in response to glucose. Importantly, chronic glucolipotoxic conditions in vitro decreased insulin gene expression, insulin content, insulin granule docking (to the plasma membrane) and insulin secretion.

Conclusions

Our results present an integrated view of the effects of chronic glucolipotoxic conditions on known and novel signaling events, in vitro, that results in reduced glucose responsiveness and insulin secretion.

【 授权许可】

   
2013 Somesh et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Prentki M, Nolan CJ: Islet beta cell failure in type 2 diabetes. J Clin Invest 2006, 116:1802-1812.
• [2]Defronzo RA: Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009, 58:773-795.
• [3]Poitout V, Amyot J, Semache M, Zarrouki B, Hagman D, Fontés G: Glucolipotoxicity of the pancreatic beta cell. Biochim Biophys Acta 1801, 2010:289-298.
• [4]Poitout V, Robertson RP: Secondary beta-cell failure in type 2 diabetes-a convergence of glucotoxicity and lipotoxicity. Endocrinology 2002, 143:339-342.
• [5]El-Assaad W, Buteau J, Peyot ML, Nolan C, Roduit R, Hardy S, Joly E, Dbaibo G, Rosenberg L, Prentki M: Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinol 2003, 144:4154-4163.
• [6]Jacqueminet S, Briaud I, Rouault C, Reach G, Poitout V: Inhibition of insulin gene expression by long-term exposure of pancreatic beta cells to palmitate is dependent on the presence of a stimulatory glucose concentration. Metabolism 2000, 49:532-536.
• [7]Shimabukuro M, Zhou YT, Levi M, Unger RH: Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 1998, 95:2498-2502.
• [8]Zhou YP, Grill VE: Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 1994, 93:870-876.
• [9]Henquin JC: Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 2000, 49:1751-1760.
• [10]Farfari S, Schulz V, Corkey B, Prentki M: Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion. Diabetes 2000, 49:718-726.
• [11]Deeney JT, Gromada J, Høy M, Olsen HL, Rhodes CJ, Prentki M, Berggren PO, Corkey BE: Acute stimulation with long chain acyl-CoA enhances exocytosis in insulin-secreting cells HIT T-15 and NMRI beta-cells. J Biol Chem 2000, 275:9363-9368.
• [12]Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney JT, Corkey BE: Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem 1992, 267:5802-5810.
• [13]Ashcroft FM, Gribble FM: ATP-sensitive K+ channels and insulin secretion: their role in health and disease. Diabetologia 1999, 42:903-919.
• [14]Zawalich WS, Zawalich KC, Kelley GG: Regulation of insulin release by phospholipase C activation in mouse islets: differential effects of glucose and neurohumoral stimulation. Endocrinol 1995, 136:4903-4909.
• [15]Persaud SJ, Jones PM, Howell SL: Activation of PKC is essential for sustained insulin secretion in response to cholinergic stimulation. Biochim Biophys Acta 1991, 1091:120-122.
• [16]Uchida T, Iwashita N, Ohara-Imaizumi M, Ogihara T, Nagai S, Choi JB, Tamura Y, Tada N, Kawamori R, Nakayama KI, Nagamatsu S, Watada H: Protein kinase C delta plays a non-redundant role in insulin secretion in pancreatic beta cells. J Biol Chem 2007, 282:2707-2716.
• [17]Dyachok O, Idevall-Hagren O, Sagetorp J, Tian G, Wuttke A, Arrieumerlou C, Akusjärvi G, Gylfe E, Tengholm A: Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion. Cell Metab 2008, 8:26-37.
• [18]Koya D, King GL: Protein kinase C activation and the development of diabetic complications. Diabetes 1998, 47:859-866.
• [19]Hagman DK, Latour MG, Chakrabarti SK, Fontes G, Amyot J, Tremblay C, Semache M, Lausier JA, Roskens V, et al.: Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets. Diabetes 2008, 57:424-431.
• [20]Hou JC, Min L, Pessin JE: Insulin granule biogenesis, trafficking and exocytosis. Vitam Horm 2009, 80:473-506.
• [21]Wang Z, Thurmond DC: Mechanisms of biphasic insulin-granule exocytosis - roles of the cytoskeleton, small GTPases and SNARE proteins. J Cell Sci 2009, 122:893-903.
• [22]Unger RH, Grundy S: Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia 1985, 28:119-121.
• [23]Unger RH: Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 1995, 44:863-870.
• [24]Poitout V: Glucolipotoxicity of the pancreatic beta-cell: myth or reality? Biochem Soc Trans 2008, 36:901-904.
• [25]Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, Bajaj M, Mandarino L, DeFronzo R, Cusi K: A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 2003, 52:2461-2474.
• [26]Poitout V, Robertson RP: Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 2008, 29:351-366.
• [27]El-Assaad W, Joly E, Barbeau A, Sladek R, Buteau J, Maestre I, Pepin E, Zhao S, Iglesias J, et al.: Glucolipotoxicity alters lipid partitioning and causes mitochondrial dysfunction, cholesterol, and ceramide deposition and reactive oxygen species production in INS832/13 ß-cells. Endocrinology 2010, 151:3061-3073.
• [28]Abaraviciene SM, Lundquist I, Salehi A: Rosiglitazone counteracts palmitate-induced beta-cell dysfunction by suppression of MAP kinase, inducible nitric oxide synthase and caspase 3 activities. Cell Mol Life Sci 2008, 65:2256-2265.
• [29]Tanabe K, Liu Y, Hasan SD, Martinez SC, Cras-Méneur C, Welling CM, Bernal-Mizrachi E, Tanizawa Y, Rhodes CJ, Zmuda E, et al.: Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation. PLoS One 2011, 6:e18146.
• [30]Gremlich S, Bonny C, Waeber G, Thorens B: Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J Biol Chem 1997, 272:30261-30269.
• [31]Matschinsky FM, Glaser B, Magnuson MA: Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 1998, 47:307-315.
• [32]Han J, Liu YQ: Reduction of islet pyruvate carboxylase activity might be related to the development of type 2 diabetes mellitus in Agouti-K mice. J Endocrinol 2010, 204:143-152.
• [33]Marshall C, Hitman GA, Cassell PG, Turner MD: Effect of glucolipotoxicity and rosiglitazone upon insulin secretion. Biochem Biophys Res Commun 2007, 356:756-762.
• [34]Guay C, Madiraju SR, Aumais A, Joly E, Prentki M: A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion. J Biol Chem 2007, 282:35657-35665.
• [35]Poitout V: The ins and outs of fatty acids on the pancreatic beta cell. Trends Endocrinol Metab 2003, 14:201-203.
• [36]Broca C, Brennan L, Petit P, Newsholme P, Maechler P: Mitochondria-derived glutamate at the interplay between branched-chain amino acid and glucose-induced insulin secretion. FEBS Lett 2003, 545:167-172.
• [37]Plant TD: Properties and calcium-dependent inactivation of calcium currents in cultured mouse pancreatic B-cells. J Physiol 1988, 404:731-747.
• [38]Maruyama T, Kanaji T, Nakade S, Kanno T, Mikoshiba K: 2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+ release. J Biochem 1997, 122:498-505.
• [39]Tian Y, Laychock SG: Protein Kinase C and Calcium Regulation of Adenylyl Cyclase in Isolated Rat Pancreatic Islets. Diabetes 2001, 50:2505-2513.
• [40]Roger B, Papin J, Vacher P, Raoux M, Mulot A, Dubois M, Kerr-Conte J, Voy BH, Pattou F, et al.: Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells. Diabetologia 2011, 54:390-402.
• [41]Kato T, Shimano H, Yamamoto T, Yokoo T, Endo Y, Ishikawa M, Matsuzaka T, Nakagawa Y, Kumadaki S, et al.: Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice. Cell Metab 2006, 4:143-154.
• [42]Olofsson CS, Collins S, Bengtsson M, Eliasson L, Salehi A, Shimomura K, Tarasov A, Holm C, Ashcroft F, Rorsman P: Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane. Diabetes 2007, 56:1888-1897.
• [43]Daniel S, Noda M, Straub SG, Sharp GW: Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion. Diabetes 1999, 48:1686-1690.
• [44]Gwiazda KS, Yang TL, Lin Y, Johnson JD: Effects of palmitate on ER and cytosolic Ca2+ homeostasis in beta-cells. Am J Physiol Endocrinol Metab 2009, 296:E690-E701.
• [45]Hajri T, Han XX, Bonen A, Abumrad NA: Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. J Clin Invest 2002, 109:1381-1389.
• [46]Wallin T, Ma Z, Ogata H, Jørgensen IH, Iezzi M, Wang H, Wollheim CB, Björklund A: Facilitation of fatty acid uptake by CD36 in insulin-producing cells reduces fatty-acid-induced insulin secretion and glucose regulation of fatty acid oxidation. Biochim Biophys Acta 1801, 2010:191-197.
• [47]Maechler P, Wollheim CB: Mitochondrial signals in glucose-stimulated insulin secretion in the beta cell. J Physiol 2000, 529:49-56.
• [48]Jang YO, Quan X, Das R, Xu S, Chung CH, Ahn CM, Baik SK, Kong ID, Park KS, Kim MY: High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells. BMC Gastroenterol 2012, 12:4. BioMed Central Full Text